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通过基于结构的虚拟查来识别强大的ADCK3抑制剂

Peng Gao¹, Mitali Tambe¹, Catherine Z Chen¹

¹Therapeutics Development Branch, Division of Preclinical Innovation, National Center for Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States.

Journal of chemical information and modeling

|July 18, 2024

概括

研究人员发现了ADCK3的新型小分子抑制剂,ADCK3是一种参与辅酶Q10生物合成的蛋白质激酶. 这些通过虚拟查识别的选择性抑制剂提供了作为化学探针来理解ADCK3的潜力.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

ADCK3是一种非典型的蛋白激酶,对辅酶Q10 (CoQ10) 生物合成至关重要.
在ADCK3中发生的突变导致CoQ10缺乏和无氧,突出显示了它的重要性.
ADCK3的确切功能仍然难以捉摸,需要化学工具进行研究.

研究的目的:

通过基于结构的虚拟查,发现ADCK3的新型小分子抑制剂.
确定可以作为化学探针来阐明ADCK3功能的选择性抑制剂.
为开发针对ADCK3相关疾病的治疗剂提供基础.

主要方法:

大约17万种化合物的基于结构的虚拟选 (VS).
基于ADCK3活性部位分析的药模型的开发.
针对p38酶的命中验证和选择性分析的生物化学测试.
分子动力学 (MD) 和元动力学模拟来预测结合模式.

主要成果:

确定了一系列新的ADCK3抑制剂.
确认了129种化合物作为ADCK3抑制剂,其中114种对p38.8具有选择性.
MD模拟揭示了抑制剂和ADCK3活性部位残留物之间的关键相互作用.

结论:

该研究成功地确定了ADCK3.3的选择性小分子抑制剂.
这些化合物代表了进一步药物开发和机制研究的有希望的起点.
这些发现有助于理解ADCK3在CoQ10生物合成和相关疾病中的作用.

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